Sodium Azide → HCID 121266525, compound

Temperature

95 °C

A mixture of (4a′R,11b′R)-2′-amino-10′-bromo-11b′-methyl-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazine]-4′,4′-dioxide (1.08 g, 2.70 mmol), (+)-sodium 1-ascorbate (0.053 g, 0.270 mmol), sodium azide (0.526 g, 8.09 mmol), and copper(i) iodide (0.103 g, 0.540 mmol) was purged with N2 followed by the addition of (1r,2r)-(−)-n,n″-dimethylcyclohexane-1,2-diamine (0.128 ml, 0.809 mmol) and EtOH/water (2/0.5 mL). The resulting mixture was heated at 95° C. for 3 h. The mixture was brought to rt, poured into a 9:1 mixture of saturated NH4Cl/NH4OH and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to afford (4a′R,11b′R)-2′-amino-10′-azido-11b′-methyl-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazine]-4′,4′-dioxide to be used without further purification. This product was dissolved in THF (20 mL) and DMF (10 mL) followed by the addition of triethylamine (0.450 ml, 3.24 mmol) and di-tert-butyl dicarbonate (0.707 g, 3.24 mmol) and the resulting mixture was stirred at rt over the weekend. The mixture was poured into saturated NH4Cl and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to afford tert-butyl ((4a′R,11b′R)-10′-azido-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate as a yellow product. The yellow residue was poured into water (50 mL) and extracted again with EtOAc to remove DMF. The combined organics were dried over Na2SO4, filtered and concentrated. The yellow oil obtained was dissolved in THF/water (10/5 mL) followed by the addition of trimethyl phosphine (0.559 ml, 5.40 mmol) and the resulting mixture was stirred at rt for 1.5 h. Some starting material was still observed, so more trimethyl phosphine (0.559 ml, 5.40 mmol) was added and stirred for 1 h more. The reaction was poured into water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-100% EtOAc/hexanes to afford a pale yellow solid as tert-butyl ((4a′R,11b′R)-10′-amino-11b′-methyl-4′,4′-dioxido-4a′,5′,6′,11b′-tetrahydrospiro[cyclobutane-1,3′-pyrido[3′,2′:6,7]oxepino[4,5-b][1,4]thiazin]-2′-yl)carbamate (0.300 g, 0.687 mmol, 25.5% yield). LC/MS (ESI+) m/z=437 (M+H).

1. customwas purged with N2
2. customwas brought to rt
3. extractionextracted with EtOAc
4. dry with materialThe combined organics were dried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated

ORD record

ord-ea4428798cc84e72b5dd3c5fb955d320

Source dataset

uspto-grants-2016_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09309263B2